Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, 10010, USA.
Department of Urology, New York University Langone Medical Center, New York, NY, 10016, USA.
Oncogene. 2019 Jun;38(24):4700-4714. doi: 10.1038/s41388-019-0745-2. Epub 2019 Feb 11.
Prostate cancer (PCa) initiation and progression requires activation of numerous oncogenic signaling pathways. Nuclear-cytoplasmic transport of oncogenic factors is mediated by Karyopherin proteins during cell transformation. However, the role of nuclear transporter proteins in PCa progression has not been well defined. Here, we report that the KPNB1, a key member of Karyopherin beta subunits, is highly expressed in advanced prostate cancers. Further study showed that targeting KPNB1 suppressed the proliferation of prostate cancer cells. The knockdown of KPNB1 reduced nuclear translocation of c-Myc, the expression of downstream cell cycle modulators, and phosphorylation of regulator of chromatin condensation 1 (RCC1), a key protein for spindle assembly during mitosis. Meanwhile, CHIP assay demonstrated the binding of c-Myc to KPNB1 promoter region, which indicated a positive feedback regulation of KPNB1 expression mediated by the c-Myc. In addition, NF-κB subunit p50 translocation to nuclei was blocked by KPNB1 inhibition, which led to an increase in apoptosis and a decrease in tumor sphere formation of PCa cells. Furthermore, subcutaneous xenograft tumor models with a stable knockdown of KPNB1 in C42B PCa cells validated that the inhibition of KPNB1 could suppress the growth of prostate tumor in vivo. Moreover, the intravenously administration of importazole, a specific inhibitor for KPNB1, effectively reduced PCa tumor size and weight in mice inoculated with PC3 PCa cells. In summary, our data established the functional link between KPNB1 and PCa prone c-Myc, NF-kB, and cell cycle modulators. More importantly, inhibition of KPNB1 could be a new therapeutic target for PCa treatment.
前列腺癌 (PCa) 的发生和发展需要激活许多致癌信号通路。在细胞转化过程中，核质转运的致癌因子由核孔蛋白复合物介导。然而，核转运蛋白在 PCa 进展中的作用尚未得到很好的定义。在这里，我们报告 Karyopherin β 亚基的关键成员 KPNB1 在晚期前列腺癌中高度表达。进一步的研究表明，靶向 KPNB1 抑制了前列腺癌细胞的增殖。KPNB1 的敲低减少了 c-Myc 的核转位、下游细胞周期调节剂的表达以及染色质凝聚调节剂 1 (RCC1) 的磷酸化，RCC1 是有丝分裂过程中纺锤体组装的关键蛋白。同时，CHIP 实验表明 c-Myc 与 KPNB1 启动子区域结合，这表明 c-Myc 介导的 KPNB1 表达的正反馈调节。此外，KPNB1 抑制阻断了 NF-κB 亚基 p50 向核内的易位，导致 PCa 细胞的凋亡增加和肿瘤球体形成减少。此外，在 C42B PCa 细胞中稳定敲低 KPNB1 的皮下异种移植肿瘤模型验证了抑制 KPNB1 可以抑制体内前列腺肿瘤的生长。此外，进口唑，一种 KPNB1 的特异性抑制剂，静脉给药可有效减小接种 PC3 PCa 细胞的小鼠的 PCa 肿瘤大小和重量。总之，我们的数据建立了 KPNB1 与 PCa 易感性 c-Myc、NF-κB 和细胞周期调节剂之间的功能联系。更重要的是，抑制 KPNB1 可能成为治疗 PCa 的新治疗靶点。
